Stimuli-responsive PEG-like polymer-based drug delivery platform
Inventors
Chilkoti, Ashutosh • Ozer, Imran
Assignees
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Publication Number
US-12257308-B2
Publication Date
2025-03-25
Expiration Date
2039-04-30
Abstract
Described herein are thermally responsive polymer-therapeutic molecule conjugates comprising a therapeutic molecule conjugated to a thermally responsive polymer with an acrylate, methacrylate, acrylamide, and/or methacrylamide backbone and a plurality of oligoethylene glycol side chains.
Core Innovation
The invention provides a thermally responsive polymer-therapeutic molecule conjugate that comprises a backbone with repeating monomer units selected from acrylate, methacrylate, acrylamide, methacrylamide, or their combinations, and a plurality of oligoethylene glycol side chains, with each side chain containing two or three ethylene glycol monomers in tandem. A therapeutic molecule is covalently conjugated to this backbone. The engineered structure is designed such that the conjugate exhibits a transition temperature between 23° C. and 40° C., facilitating a phase shift from soluble to insoluble (depot formation) near physiological temperatures, but allowing solubility at room temperature for easy injection.
The invention addresses a significant challenge in the delivery of therapeutic biomolecules, which typically suffer from short plasma half-life and poor stability, resulting in rapid elimination and the necessity of frequent dosing. While PEGylation has been the conventional solution to improve stability and pharmacokinetics, it presents issues such as immunogenicity and adverse reactions due to induced or pre-existing anti-PEG antibodies. This has resulted in early termination of clinical trials and diminished safety and efficacy in PEGylated therapeutics. Hence, there remains a need for a delivery system that can maintain drug stability and half-life without provoking immune responses associated with PEG.
The disclosed polymer platform, exemplified by poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA), allows for site-specific and stoichiometric conjugation to various types of therapeutic molecules, including peptides and proteins. The system's phase behavior is designed to be reversible and tunable, enabling depot formation at injection sites for sustained release of drugs into the bloodstream. Notably, the conjugates can avoid unwanted interactions with anti-PEG antibodies and improve in vivo efficacy by providing localized, sustained, and controlled release, as demonstrated using exendin-POEGMA conjugates for glycemic control in diabetic animal models.
Claims Coverage
The patent contains three independent claims, each defining key inventive features for the thermally responsive polymer-therapeutic molecule conjugate, a drug depot, and a method of treatment.
Thermally responsive polymer-therapeutic molecule conjugate structure
A conjugate comprising: - A backbone of 100 to 600 repeating monomer units selected from acrylate, methacrylate, acrylamide, methacrylamide, and their combinations. - A plurality of oligoethylene glycol side chains, each covalently attached to the backbone at one end, with each side chain consisting of two or three ethylene glycol monomers in tandem, and between 45% and 85% of the side chains containing two such monomers. - A therapeutic molecule conjugated to the backbone. - The conjugate displaying a transition temperature between 23° C. and 40° C.
Drug depot comprising the thermally responsive conjugate
A drug depot which contains the above-defined thermally responsive polymer-therapeutic molecule conjugate. Upon administration, the conjugate forms a drug depot as a result of its thermally responsive properties.
Method of treating a disease or disorder
A method involving: - Administering a therapeutically effective amount of the thermally responsive polymer-therapeutic molecule conjugate, as defined above, to a subject in need. - The method enables treatment through the formation of a drug depot upon administration, sustaining the release of the therapeutic molecule for enhanced therapeutic effect.
The independent claims cover the structure of a thermally responsive polymer-therapeutic molecule conjugate with specific side chain composition and transition temperature, the creation of a drug depot utilizing this conjugate, and a method of treatment leveraging depot formation for sustained therapeutic delivery.
Stated Advantages
The platform allows for efficient depot formulation with improved pharmacokinetics, necessitating less frequent injections and increasing patient compliance.
The system provides versatility by enabling tunable release profiles and desired pharmacokinetics due to its controllable amphiphilicity.
Local delivery to a region of interest is achievable, allowing sustained release at a selected site and reducing unwanted side effects from systemic exposure.
The conjugates are not subject to harmful interaction with pre-existing anti-PEG antibodies and offer potential to address PEG antigenicity problems.
Conjugates show improved solubility, stability, pharmacokinetics, and reduced immunogenicity compared to non-conjugated therapeutics or traditional PEGylation.
Depot formation at physiological temperature enables a controlled and sustained release of the drug from the injection site.
Documented Applications
Treatment of diseases or disorders, including but not limited to cancers, metabolic diseases, autoimmune diseases, cardiovascular diseases, respiratory diseases, allergies, and orthopedic disorders.
Treatment of metabolic disorders such as type 1 or type 2 diabetes, hyperglycemia, and impaired glucose tolerance when the therapeutic molecule includes a GLP-1 receptor agonist, exendin, or insulin.
Treatment of bleeding disorders such as hemophilia, post-surgical bleeding, anticoagulation-induced bleeding, thrombocytopenia, factor VII deficiency, factor XI deficiency, and intracranial hemorrhage when the therapeutic molecule is a blood clotting factor.
Use as a depot drug delivery system for sustained and controlled release of therapeutic molecules after subcutaneous injection.
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